OSTEOCLASTOGENESIS INHIBITORY FACTOR SUPPRESSES OSTEOCLAST SURVIVAL BY INTETFERING IN THE INTERACTION OF STROMAL CELLS WITH OSTEOCLAST

Osteoclastogenesis inhibitory factor (OCIF) was originally identified as a factor inhibiting osteoclast (OC) formation. The number of OC in rats treated with OCIF decreased, suggesting that OCIF inhibits OC for mation in vivo; however, it is also possible that OCIF affects the num ber of OC by promoting apoptosis of OC. To address this issue, the eff ects of OCIF on the survival of OC were examined using well establishe d mouse culture systems. OCIF dose-dependently inhibited OC formation in mouse marrow cultures. Addition of OCIF during day 0-3 did not alte r the peak levels of OC formation on day 7 and 8. However, the additio n of OCIF during day 5 and thereafter resulted in the rapid decrease o f the number of OC, OCIF inhibited the survival of OC formed in mouse marrow cultures in dose- and time-dependent manners. The involvement o f stromal cells in OC survival was examined using crude and stromal ce ll-depleted OC populations. OCIF dramatically inhibited the survival o f crude OC populations rich with stromal cells. However, in stromal ce ll-depleted OC populations, OC spontaneously decreased in the absence of OCIF and OCIF did not enhance the decrease further at least up to 4 8 h. Apoptotic OC were detected in detached cell populations treated w ith OCIF in mouse marrow cultures and a specific inhibitor for caspase -3 rescued the death of OC. OCIF mutant lacking the death domain homol ogous regions inhibited OC survival, though the potency was much less than native OCIF. Taken together, OCIF inhibited not only OC recruitme nt but also OC survival. OCIF inhibited OC survival by interfering the interaction of stromal cells with OC. (C) 1998 Academic Press.